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EP0375063B1 - Granulates for multiparticulate controlled-release oral compositions - Google Patents

Granulates for multiparticulate controlled-release oral compositions Download PDF

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Publication number
EP0375063B1
EP0375063B1 EP89203243A EP89203243A EP0375063B1 EP 0375063 B1 EP0375063 B1 EP 0375063B1 EP 89203243 A EP89203243 A EP 89203243A EP 89203243 A EP89203243 A EP 89203243A EP 0375063 B1 EP0375063 B1 EP 0375063B1
Authority
EP
European Patent Office
Prior art keywords
release
granulate according
granulate
acid
biologically active
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP89203243A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP0375063A1 (en
Inventor
Jan Willem Groenendaal
Edoaldus Vork
Hendrikus Adrianus Gerardus De Ronde
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Astellas Pharma Europe BV
Original Assignee
Yamanouchi Europe BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yamanouchi Europe BV filed Critical Yamanouchi Europe BV
Priority to AT89203243T priority Critical patent/ATE94058T1/de
Publication of EP0375063A1 publication Critical patent/EP0375063A1/en
Application granted granted Critical
Publication of EP0375063B1 publication Critical patent/EP0375063B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This invention relates to granulates for multi-particulate controlled-release oral compositions comprising biologically active substances, targeted to predetermined parts of the intestine and especially to the lower part thereof, and to oral compositions, containing such granulates.
  • a further development is to use the concept of solid dispersion of the active principle in the release-modifying substance as an alternative to coating the active principle with the release-modifying substance.
  • a solid dispersion which is to be clearly distinguished from simple mechanical mixes, has been defined as a dispersion of one or more active ingredients in an inert excipient at solid state prepared by the melting (fusion), solvent, or melting-solvent method (J.L. Ford, Pharm.Acta Helv. 67 ,(1986),69).
  • the concept of solid dispersion was introduced by K. Sekiguchi and N. Obi (Chem. Pharm. Bull. 9 , (1961) 866), to improve the bio-availability of a poorly water-soluble drug by dispersing it in a water-soluble excipient.
  • Japanese Patent Application (Kokai) 61,078,733 discloses an amorphous solid preparation intended to dissolve ir. the intestine, comprising (a) a non-steroid type anti-inflammatory agent such as indomethacin and (b) one or more pH-dependent high molecular compounds, such as a copolymer of methacrylic acid and methyl methacrylate. It is manufactured by dissolving (a) and (b) in a common solvent, removing the solvent and pulverising the solid formed. Only grains falling within the required size are used, which of course involves loss of substance. Besides, when these grains are to be further processed into tablets, they have to be granulated first, a process in the course of which there exists a danger of adversely influencing the glass-like consistency of the solid dispersion, thus defeating its purpose of acid resistance.
  • a non-steroid type anti-inflammatory agent such as indomethacin
  • pH-dependent high molecular compounds such as a copolymer of me
  • this method is not suitable for solid dispersions of the release-limiting (pH-independent) type since these solid dispersions will allow already in the acid environment of the stomach the occurrence of aqueous diffusion, which will dissolve the cores, changing the form of the particles and making the release characteristics unpredictable and uncontrollable.
  • water-insoluble carrier particles do not have the above disadvantages, and that granulates for multiparticulate oral compositions wherein a biologically active compound is incorporated in solid dispersion with an acid-resistant or release-limiting compound can be prepared more efficiently and effectively by mixing this solid dispersion with water-insoluble carrier particles.
  • water-insoluble carrier particles When water-insoluble carrier particles are used, they can simply be mixed with the dispersion before it is solidified, without any need to actively deposit the solid on the carrier cores. After the complete mixture has solidified, it is further processed to a granulate according to granulation methods known in the art, such as oscillating-sieving or extrusion.
  • the process according to the invention is very versatile since it is applicable to both acid-resistant and release-limiting preparations.
  • the process is also very efficient since no special apparatus is required for the simple step of mixing the water-insoluble carrier particles with the dispersion, and since due to the granules being irregular in shape and porous they can be immediately compressed into tablets.
  • the present invention provides a method for preparing a granulate for a multiparticulate oral composition based on the concept of solid dispersion, whereby a biologically active substance is dispersed in an acid-resistant or release-limiting substance using the melting, the solvent or the melting-solvent method, characterized in that before the dispersion is solidified it is mixed with water-insoluble carrier particles whereafter the complete mixture is further processed according to granulation methods known in the art.
  • the invention also provides granulates for multi-particulate oral compositions comprising a biologically active substance in solid dispersion with an acid-resistant and/or a release-limiting compound, characterized in that the solid dispersion is mixed with water-insoluble carrier particles.
  • any biologically active compound can be incorporated in the granulates for multiparticulate oral compositions of this invention, and in particular those compounds, e.g. the therapeutic (poly) peptides, which are sensitive to acid or to digestive enzymes and those which are disagreeable to the stomach, but that the main application of this invention lies with compounds which are meant to act locally in the intestine.
  • the latter are corticosteroids and non-steroidal anti-inflammatory compounds, especially beclomethasone 17,21-dipropionate and 5- or 4-amino-salicylic acid or their derivatives.
  • Further examples are bismuth compounds, especially Colloidal Bismuth Subcitrate. It will be appreciated that two or more biologically active compounds can also be incorporated in a composition according to the invention.
  • Acid-resistant and release-limiting compounds to be used in the compositions according to the invention may be any one or a combination of the compounds known for this purpose in the art.
  • Examples of known acid-resistant compounds are polymethacrylates, especially those known under the name of EUDRAGIT®-L and -S, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, and shellac.
  • EUDRAGIT®-S has been found to be a preferable acid resistant compound.
  • release-limiting compounds examples include the polymethacrylates known under the name EUDRAGIT®-RL,-RS and -NE, ethylcellulose and polyvinyl acetate, fatty acids such as stearic acid, fatty acid esters such as PRECIROL®, long chain aliphatic alcohols such as cetyl, stearyl, cetostearyl and myristyl alcohol, hydrogenated vegetable oils such as hydrogenated castor oil and hydrogenated cottonseed oil, waxes such as bees wax and distilled monoglycerides such as glyceryl monostearate.
  • EUDRAGIT®-RS has been found to be a preferable release-limiting compound.
  • the percentage of the biologically active compound (w/w) in the solid dispersion can vary between 0.01 and 99%, depending on the the components used.
  • the biologically active compound is a corticosteroid such as beclomethasone 17,21-dipropionate its percentage (w/w) in the solid dispersion is preferably 0.1-40%, more preferably 5-15%.
  • the biologically active compound is a non-steroidal anti-inflammatory compound such as 5- or 4-amino-salicylic acid its percentage (w/w) in the solid dispersion is preferably 20-90%, more preferably 50-80%.
  • an organic or an aqueous solvent may be used for the dispersion of the biologically active material in the acid-resistant or release-limiting substance.
  • methylene chloride As an organic solvent, methylene chloride has been found to be useful to disperse steroids, such as beclomethasone 17,21-dipropionate, in release-limiting substances.
  • steroids such as beclomethasone 17,21-dipropionate
  • a mixture of about equal weights of ethanol and methylene chloride has been found to be very useful as the solvent.
  • aqueous polymeric dispersions When an aqueous solvent is employed to disperse a water-soluble biologically active substance, e.g. a therapeutic peptide, in the acid-resistant or release-limiting compound, aqueous polymeric dispersions have been found to be particularly useful as the aqueous solvent.
  • aqueous dispersions of polymethacrylates such as EUDRAGIT®-L-30-D, EUDRAGIT®-RL-30-D, EUDRAGIT®-RS-30-D and EUDRAGIT®-NE-30,-40 or -50D
  • aqueous dispersions of submicron ethylcellulose spheres AQUACOAT®
  • aqueous dispersions of submicron cellulose acetate phthalate spheres AQUATERIC®
  • water-insoluble carriers examples include powdered cellulose, microcrystalline cellulose, starches, colloidal silicon dioxide, bentonite, magnesium aluminum silicate and kaolin.
  • microcrystalline cellulose such as is known under the proprietary name AVICEL®, has been found to be a preferred carrier.
  • the preferred mean size of the carrier particles is about 0.1 mm, and the preferred mean particle size of the granulate (carrier plus solid dispersion) is 0.1-2 mm, more preferably 0.5-1.2 mm.
  • the granulates according to the invention can be incorporated in any of the preparations for oral application known in the art, such as sachets, capsules and,- preferably, tablets, optionally also containing pharmaceutically acceptable excipients.
  • Tablets containing the granulates according to the invention have the practical advantages which are inherent to tablets in general, and additionally they have the advantage of being multi-particulate compositions, in that they disintegrate in the stomach, releasing the granules, which are small enough to leave the stomach rapidly and reliably.
  • tablets containing the granulates according to the invention can be left to disintegrate in a small amount of water, rendering a homogeneous, drinkable dispersion.
  • the invention therefore also provides multiparticulate controlled-release oral compositions, in particular tablets, containing the granulates of the invention.
  • the batch of granules now ready for further processing, had a total weight of about 500 grams. 50 grams of it had a free volume of 170 ml. Its residual content of ethanol and methylene chloride, determined by GLC, was 1.5% and 0.015%, respectively.
  • the granules had the following particle size distribution:
  • the content of beclomethasone 17,21-dipropionate in the granules was 3.0% w/w, as determined by HPLC.
  • the disintegration adjuvants KOLLIDON®-CL and AVICEL® PH 102 both in the quantities of 28 g, were added to 500 g of the granules of Example 1 and mixed during 10 minutes. Subsequently 5.5 g of the lubricant magnesium stearate were added and mixed during a further 2 minutes. The mass was then fed to an excenter press tabletting machine, producing concave tablets having a diameter of 7 mm, a hardness of 9-11 kp and a disintegrating time (into the granules ), in 0.1 N HCl at 37°C of 3-5 minutes. The tablets weighed 112.3 mg apiece, containing 3 mg beclomethasone 17,21-dipropionate and 20 mg EUDRAGIT®-S.
  • Beclomethasone 17,21-dipropionate was detected in samples of the medium taken at different time, whereby the HPLC method was used for quantification against a standard of 6 ⁇ g/ml beclomethasone 17, 21-dipropionate in phosphate buffer of pH 7.0 + 2% CETOMACROGOL® 1000.
  • the content of beclomethasone 17,21-dipropionate in the granules was 2.75% w/w, as determined by HPLC.
  • the disintegration adjuvants KOLLIDON®-CL and AVICEL® PH 102 both in the quantities of 12.5 g, were added to 222.5 g of the granules of Example 3 and mixed during 10 minutes. Subsequently 2.5 g of the lubricant magnesium stearate were added and mixed during a further 2 minutes. The mass was then fed to an excenter press tabletting machine, producing concave tablets having a diameter of 7 mm, a hardness of 6-7 kp and a disintegrating time (into the granules), in 0.1 N HCl at 37°C, of 3-5 minutes. The tablets weighed 117 mg apiece, containing 3 mg beclomethasone 17,21-dipropionate and 26 mg EUDRAGIT®-RL.
  • the dissolution rate of these granules was tested according to USP-XXI at 37°C, with the paddle stirring at 100 rpm. 555 mg granules were put in 1000 ml of phosphate buffer medium of pH 7.5 to which was added 0.1% PLURONIC® F68. At time intervals up to 12 hours the absorbance at 326 nm was measured using a spectrophotometer equiped with a continuous-flow sampling system. The 5-amino-salicylic acid content was calculated using the absorbance value of a standard of 260 ⁇ g/ml of 5-amino-salicylic acid in phosphate buffer of pH 7.5, containing 0.1% PLURONIC® F68.

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  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP89203243A 1988-12-20 1989-12-18 Granulates for multiparticulate controlled-release oral compositions Expired - Lifetime EP0375063B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT89203243T ATE94058T1 (de) 1988-12-20 1989-12-18 Verzoegerte multipartikel-zusammensetzung fuer orale anwendung.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP88202983 1988-12-20
EP88202983 1988-12-20

Publications (2)

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EP0375063A1 EP0375063A1 (en) 1990-06-27
EP0375063B1 true EP0375063B1 (en) 1993-09-08

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EP89203243A Expired - Lifetime EP0375063B1 (en) 1988-12-20 1989-12-18 Granulates for multiparticulate controlled-release oral compositions

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EP (1) EP0375063B1 (pt)
JP (1) JPH02223513A (pt)
KR (1) KR900009059A (pt)
CN (1) CN1044398A (pt)
AU (1) AU622745B2 (pt)
CA (1) CA2005992A1 (pt)
DE (1) DE68909023T2 (pt)
DK (1) DK647689A (pt)
ES (1) ES2059710T3 (pt)
FI (1) FI896062A7 (pt)
HU (1) HU203279B (pt)
IL (1) IL92343A0 (pt)
NO (1) NO176125C (pt)
NZ (1) NZ231828A (pt)
PT (1) PT92616B (pt)
ZA (1) ZA899732B (pt)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5958452A (en) 1994-11-04 1999-09-28 Euro-Celtique, S.A. Extruded orally administrable opioid formulations
US6068855A (en) 1994-11-03 2000-05-30 Euro-Celtique S. A. Pharmaceutical composition containing a fusible carrier and method for producing the same
US8293273B2 (en) 1999-06-14 2012-10-23 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition
US8895064B2 (en) 1999-06-14 2014-11-25 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition
US10154964B2 (en) 2011-09-07 2018-12-18 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition

Families Citing this family (32)

* Cited by examiner, † Cited by third party
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US5776493A (en) * 1989-07-14 1998-07-07 Alza Corporation Oral osmotic device for delivery of nystatin with hydrogel driving member
GEP19971086B (en) * 1991-02-22 1997-12-02 Tillotts Pharma Ag Peroral Pharmaceutically Dispensed Form for Selective Introducing of the Medicine into the Intestine
TW212139B (pt) * 1991-04-15 1993-09-01 Yamanouchi Pharma Co Ltd
EP0580860B2 (en) * 1991-04-16 2004-12-15 Nippon Shinyaku Company, Limited Method of manufacturing solid dispersion
US5248310A (en) * 1992-03-27 1993-09-28 Alza Corporation Oral osmotic device with hydrogel driving member
US5512299A (en) * 1992-03-30 1996-04-30 Alza Corporation Method of treating oral inflammatory disease
WO1995016451A1 (fr) * 1992-06-22 1995-06-22 Franck Arno Gouchet Comprimes a liberation controlee de 4-asa
FR2692484B1 (fr) * 1992-06-22 1995-06-30 Gouchet Franck Nouvelle forme galenique de 4-asa a liberation controlee.
US5395627A (en) * 1992-09-04 1995-03-07 Akzo N.V. Pharmaceutical granulate
US5573776A (en) * 1992-12-02 1996-11-12 Alza Corporation Oral osmotic device with hydrogel driving member
US6902738B2 (en) 1994-05-02 2005-06-07 Josman Laboratories, Inc. Topical oral dosage forms containing bismuth compounds
US6426085B1 (en) 1994-05-02 2002-07-30 Josman Laboratories Inc. Use of bismuth-containing compounds in topical oral dosage forms for the treatment of halitosis
US5834002A (en) 1994-05-02 1998-11-10 Josman Laboratories, Inc. Chewing gum containing colloidal bismuth subcitrate
AT403988B (de) * 1994-05-18 1998-07-27 Lannacher Heilmittel Festes orales retardpräparat
US6372784B1 (en) 1995-02-07 2002-04-16 Josman Laboratories, Inc. Bismuth-containing compounds in topical dosage forms for treatment of corneal and dermal wounds
US6379651B1 (en) 1995-02-07 2002-04-30 Josman Laboratories Oral-topical dosage forms for delivering antibacterials/antibiotics to oral cavity to eradicate H. pylori as a concomitant treatment for peptic ulcers and other gastro-intestinal diseases
IT1301947B1 (it) * 1998-07-28 2000-07-20 Chiesi Farma Spa Formulazioni farmaceutiche di beclometasone dipropionato per iltrattamento di malattie infiammatorie croniche della mucosa
DE19918325A1 (de) 1999-04-22 2000-10-26 Euro Celtique Sa Verfahren zur Herstellung von Arzneiformen mit regulierter Wirkstofffreisetzung mittels Extrusion
ITMI991316A1 (it) * 1999-06-14 2000-12-14 Cip Ninety Two 92 S A Composizioni farmaceutiche orali a rilascio modificato di mesalazina
JP4310605B2 (ja) * 2001-05-25 2009-08-12 大塚製薬株式会社 医薬用組成物
RU2195292C1 (ru) * 2001-11-29 2002-12-27 Открытое акционерное общество "Химико-фармацевтический комбинат "Акрихин" Фармацевтическая композиция, обладающая противоязвенным и антацидным действием
US20030190343A1 (en) * 2002-03-05 2003-10-09 Pfizer Inc. Palatable pharmaceutical compositions for companion animals
US10004729B2 (en) 2002-07-05 2018-06-26 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
WO2004004693A1 (en) * 2002-07-05 2004-01-15 Collgegium Pharmaceutical Abuse-deterrent pharmaceutical compositions of opiods and other drugs
US8840928B2 (en) 2002-07-05 2014-09-23 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
US8557291B2 (en) 2002-07-05 2013-10-15 Collegium Pharmaceutical, Inc. Abuse-deterrent pharmaceutical compositions of opioids and other drugs
CA2569958C (en) 2004-06-12 2016-03-22 Jane C. Hirsh Abuse-deterrent drug formulations
US20070048373A1 (en) * 2005-08-30 2007-03-01 Cima Labs Inc. Dried milled granulate and methods
US10668060B2 (en) 2009-12-10 2020-06-02 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
WO2011101734A2 (en) * 2010-02-22 2011-08-25 Lupin Limited Taste-masked powder for suspension compositions of methylprednisolone
IT1405012B1 (it) * 2010-08-06 2013-12-16 Sofar Spa Composizioni di beclometasone dipropionato in microsfere gastroresistenti a rilascio modificato e processo per il loro ottenimento
WO2017222575A1 (en) 2016-06-23 2017-12-28 Collegium Pharmaceutical, Inc. Process of making more stable abuse-deterrent oral formulations

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6068855A (en) 1994-11-03 2000-05-30 Euro-Celtique S. A. Pharmaceutical composition containing a fusible carrier and method for producing the same
US5958452A (en) 1994-11-04 1999-09-28 Euro-Celtique, S.A. Extruded orally administrable opioid formulations
US5965161A (en) 1994-11-04 1999-10-12 Euro-Celtique, S.A. Extruded multi-particulates
US6261599B1 (en) 1994-11-04 2001-07-17 Euro-Celtique, S.A. Melt-extruded orally administrable opioid formulations
US6335033B2 (en) 1994-11-04 2002-01-01 Euro-Celtique, S.A. Melt-extrusion multiparticulates
US9320716B2 (en) 1999-06-14 2016-04-26 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical compositions
US10052286B2 (en) 1999-06-14 2018-08-21 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition
US8895064B2 (en) 1999-06-14 2014-11-25 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition
US9132093B2 (en) 1999-06-14 2015-09-15 Cosmo Technologies Limited Controlled release and taste making oral pharmaceutical composition
US9192581B2 (en) 1999-06-14 2015-11-24 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition
US8293273B2 (en) 1999-06-14 2012-10-23 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition
US9532954B2 (en) 1999-06-14 2017-01-03 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical compositions
US9592203B2 (en) 1999-06-14 2017-03-14 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition
US9737489B2 (en) 1999-06-14 2017-08-22 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition
US8784888B2 (en) 1999-06-14 2014-07-22 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition
US10064878B2 (en) 1999-06-14 2018-09-04 Cosmo Technologies Ltd. Controlled release and taste masking oral pharmaceutical compositions
US10105374B2 (en) 1999-06-14 2018-10-23 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical compositions
US10143698B2 (en) 1999-06-14 2018-12-04 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical compositions
US10154964B2 (en) 2011-09-07 2018-12-18 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition
US10172799B1 (en) 2011-09-07 2019-01-08 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition
US10307375B2 (en) 2011-09-07 2019-06-04 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition
US10660858B2 (en) 2011-09-07 2020-05-26 Cosmo Technologies Limited Controlled release and taste masking oral pharmaceutical composition

Also Published As

Publication number Publication date
DK647689D0 (da) 1989-12-19
CN1044398A (zh) 1990-08-08
DK647689A (da) 1990-06-21
HU203279B (en) 1991-07-29
HUT53514A (en) 1990-11-28
NZ231828A (en) 1992-03-26
EP0375063A1 (en) 1990-06-27
NO176125B (no) 1994-10-31
NO176125C (no) 1995-02-08
PT92616B (pt) 1995-09-12
ES2059710T3 (es) 1994-11-16
NO895114L (no) 1990-06-21
FI896062A7 (fi) 1990-06-21
AU4713189A (en) 1990-06-28
FI896062A0 (fi) 1989-12-18
DE68909023T2 (de) 1994-02-03
ZA899732B (en) 1990-09-26
AU622745B2 (en) 1992-04-16
DE68909023D1 (de) 1993-10-14
KR900009059A (ko) 1990-07-02
JPH02223513A (ja) 1990-09-05
PT92616A (pt) 1990-06-29
HU896686D0 (en) 1990-02-28
NO895114D0 (no) 1989-12-19
IL92343A0 (en) 1990-07-26
CA2005992A1 (en) 1990-06-20

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